The p190 RhoGAPs, ARHGAP35, and ARHGAP5 are implicated in GnRH neuronal development: Evidence from patients with idiopathic hypogonadotropic hypogonadism, zebrafish, and in vitro GAP activity assay.

PURPOSE: The study aimed to identify novel genes for idiopathic hypogonadotropic hypogonadism (IHH). METHODS: A cohort of 1387 probands with IHH underwent exome sequencing and de novo, familial, and cohort-wide investigations. Functional studies were performed on 2 p190 Rho GTPase-activating proteins (p190 RhoGAP), ARHGAP35 and ARHGAP5, which involved in vivo modeling in larval zebrafish and an in vitro p190A-GAP activity assay. RESULTS: Rare protein-truncating variants (PTVs; n = 5) and missense variants in the RhoGAP domain (n = 7) in ARHGAP35 were identified in IHH cases (rare variant enrichment: PTV [unadjusted P = 3.1E-06] and missense [adjusted P = 4.9E-03] vs controls). Zebrafish modeling using gnrh3:egfp phenotype assessment showed that mutant larvae with deficient arhgap35a, the predominant ARHGAP35 paralog in the zebrafish brain, display decreased GnRH3-GFP+ neuronal area, a readout for IHH. In vitro GAP activity studies showed that 1 rare missense variant [ARHGAP35 p.(Arg1284Trp)] had decreased GAP activity. Rare PTVs (n = 2) also were discovered in ARHGAP5, a paralog of ARHGAP35; however, arhgap5 zebrafish mutants did not display significant GnRH3-GFP+ abnormalities. CONCLUSION: This study identified ARHGAP35 as a new autosomal dominant genetic driver for IHH and ARHGAP5 as a candidate gene for IHH. These observations suggest a novel role for the p190 RhoGAP proteins in GnRH neuronal development and integrity.

Singleton pregnancies conceived with infertility treatments and the risk of neonatal and infant mortality.

OBJECTIVES: To examine the risks of neonatal and infant mortality in relation to infertility treatment and to quantify the extent to which preterm delivery mediates this relationship. DESIGN: Cross-sectional study. SETTING: United States, 2015-2018. PATIENT(S): A total of 14,961,207 pregnancies resulting in a singleton live birth. INTERVENTION(S): Any infertility treatment, including assisted reproductive technology and fertility-enhancing drugs. MAIN OUTCOME MEASURE(S): Neonatal (<28 days) mortality. The effect measure, risk ratio (RR), and 95% confidence interval (CI) were derived from log-linear Poisson models. A causal mediation analysis of the relationship between infertility treatment and mortality associated with preterm delivery (<37 weeks) was performed. The effects of exposure misclassification and unmeasured confounding biases were assessed. RESULT(S): Any infertility treatment was documented in 1.3% (n = 198,986) of pregnancies. Infertility treatment was associated with a 51% increased risk of neonatal mortality (RR 1.51, 95% CI 1.39-1.64), with a slightly higher risk for early neonatal mortality (RR 1.57, 95% CI 1.43-1.73) than late neonatal mortality (RR 1.33, 95% CI 1.11-1.58). These risks were similar for pregnancies conceived through assisted reproductive technology and fertility-enhancing drugs. The mediation analysis showed that 72% (95% CI 59-85) of the total effect of infertility treatment on neonatal mortality was mediated through preterm delivery. In a sensitivity analysis, following corrections for exposure misclassification and unmeasured confounding biases, these risks were higher for early, but not for late, neonatal mortality. CONCLUSION(S): Pregnancies conceived with infertility treatment are associated with increased neonatal mortality, and this association is largely mediated through preterm delivery. However, given the substantial underreporting of infertility treatment, these associations must be cautiously interpreted.

A 1-year open-label trial of olanzapine in school-age children with schizophrenia.

OBJECTIVE: To determine the response of children with childhood-onset schizophrenia to a 1-year prospective, open-label trial of olanzapine. METHODS: Twenty children (age range 6-15 years) with childhood-onset Diagnostic and Statistical Manual of Mental Disorders (fourth edition) schizophrenia participated. The treating clinician was free to vary or discontinue dosing and use additional medications. Symptoms were assessed by the Brief Psychiatric Rating Scale-Child version (BPRS-C), Scale for the Assessment of Positive Symptoms, and Scale for the Assessment of Negative Symptoms. Extrapyramidal symptoms, akathisia, temperature, and weight were monitored. RESULTS: BPRS-C subscales of thought disturbance and psychomotor excitation, and the Scale for the Assessment of Positive Symptoms demonstrated significant decreases by 6 weeks of treatment; BPRS-C anxiety and the Scale for the Assessment of Negative Symptoms (SANS) showed significant improvement after 1 year of treatment. Seventy-four percent of subjects were considered treatment responders, with a greater than 20% reduction in total BPRS-C score and overall impairment of mild or better. Weight gain (body mass index) was above that expected for normal development in every child. No child developed neuroleptic-related dyskinesias. Seventy-four percent (n = 14) of patients completed this 1-year, open-label trial. Of the 5 subjects who discontinued, weight gain was noted as the reason for 4 subjects. CONCLUSIONS: Olanzapine appears useful in the treatment of childhood-onset schizophrenia, although there may be a delayed onset of benefit for anxiety and negative symptoms. Weight gain is problematic, but the emergence of dyskinesias may be rare. Additional controlled trials are indicated.

Creating school-age versions of semistructured interviews for the prodrome to schizophrenia: lessons from case reviews.

There is an increasing emphasis on identifying individuals with schizophrenia earlier and earlier in their disease process, with the assumption that earlier identification translates into earlier treatment, which translates into improved outcome. Unfortunately, one age cohort, children under 13 years of age, have been excluded from this critical alteration in clinical intervention strategy, and its associated improved clinical outcome. One of the barriers to inclusion of younger children is the lack of knowledge about diagnostic issues related to attenuated psychotic symptoms in this age sample. This report focuses on our experience with evaluating attenuated psychotic symptoms in young children, in particular subthreshold hallucinations and delusions, using semistructured interviews. The inclusion of both Caregiver and Child report sections and the addition of concrete, detailed examples of clear-conscience, non-stress-related subthreshold psychotic symptoms are likely to be necessary.